Lung cancer is the most common cause of cancer-related mortality in the world. Recent findings suggest that lung cancers can be subdivided according to mutations in specific proto-oncogenes. One subset of human lung adenocarcinomas is dependent on mutant epidermal growth factor receptor (EGFR) genes and responsive to drugs that inhibit protein-tyrosine kinases. The overall goals of this proposal are to use genetically engineered mice and cell lines derived from human lung cancers to enlarge our understanding of this subset of lung adenocarcinomas and to acquire new knowledge that might improve strategies for treating patients with this type of lung cancer. In pursuit of these goals, we will: (i) characterize the oncogenic properties of genetically designed mice carrying tetracycline-inducible transgenes that encode the two mutant forms of EGFR observed most commonly in human lung adenocarcinomas;(ii) compare the responses of mutant EGFR-induced tumors that occur after reduction of EGFR levels by withdrawal of antibiotics with those that occur after inhibition of EGFR protein-tyrosine kinase (TK) activity by administration of TK inhibitors (TKIs) recently introduced into therapy of human lung cancer;and (iii) identify components of the signaling pathways involved in the tumor-maintaining properties of mutant EGFR and the presumptive analogous properties of mutant KRAS by using cultured cells from human lung adenocarcinomas. This will entail screening for chemicals and inhibitory RNAs that may interfere with those pathways followed by validation of candidate signaling components and inhibitory chemicals by either interfering with or reversing lung tumorigenesis in transgenic animals.